The central theme of this proposal is the molecular and biological characterization of a new programmed cell death (PCD) pathway termed "programmed necrosis". The importance of this proposal is highlighted by the abundant evidence illustrating the key roles PCD play in many biological processes including development, cancers, autoimmune diseases and infections by viruses and bacteria. Unlike apoptosis, programmed necrosis is characterized by rapid rupture of the cell membrane without chromatin condensation and therefore can result in local tissue inflammation. Because of the importance of inflammation in triggering an immune response, cell death by programmed necrosis may have a general immuno-stimulatory effect. This grant application will examine the molecular regulation of programmed necrosis. Specifically, the role of caspases and TRAF2 in regulating programmed necrosis will be examined. Another objective of the proposal is to examine the biological role of this pathway using vaccinia virus infection as a model. Transgenic mice expressing an inhibitor of programmed necrosis will be tested for their response to vaccinia infection. These experiments will provide important information on the role of programmed necrosis in the induction of immune responses, and the knowledge gained from these studies may aid the development of better vaccines. Moreover, controlling cell death may offer a novel approach to treating autoimmune diseases. [unreadable] [unreadable]